Regulation and Function of hTERT in Human Cells

hTERT 在人类细胞中的调控和功能

• 批准号: 8239518
• 负责人: William C. Hahn
• 金额: $ 34.48万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239518
• 关键词: Adult; Aging; Animal Model; Animals; Aplastic Anemia; Biochemical; Biochemical Genetics; Biological; Biology; Cartilage; Catalytic Domain; Cell physiology; Cells; Cellular Stress; Chromatin; Chromatin Structure; Chromosomal Stability; Complex; Defect; Development; Disease; Double-Stranded RNA; Dyskeratosis Congenita; Endoribonucleases; Failure; Fibroblasts; Foundations; Funding; GTP-Binding Proteins; Genes; Genetically Engineered Mouse; Goals; Hair; Hamman-Rich syndrome; Hematopoietic; Heterochromatin; Homeostasis; Human; Inherited; Length; Link; Longevity; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mitochondrial RNA; Molecular; Mutate; Mutation; Neoplastic Cell Transformation; Normal Cell; Normal tissue morphology; Oncogene Activation; Pathogenesis; Patients; Phenotype; Play; Process; Protein Binding; Proteins; RNA; RNA Interference; RNA Processing; RNA-Directed RNA Polymerase; Regulation; Ribonucleases; Role; Skin; Small Interfering RNA; Stem cells; Stimulus; Structure; Syndrome; Telomerase; Telomere Maintenance; Therapeutic Agents; Tissues; Work; base; cancer cell; cell transformation; endoribonuclease; human TERT protein; insight; loss of function; novel; novel therapeutics; protein complex; public health relevance; regenerative; senescence; telomerase reverse transcriptase; telomere; translational study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Telomere homeostasis regulates both chromosomal stability and cell replicative lifespan in mammalian cells. As a consequence, alterations in telomere biology play critical roles in the pathogenesis of human cancer and may contribute to aging. Indeed, studies in both human and animal models indicate that telomeres and telomerase, the reverse transcriptase that maintains telomere structure, serve dual roles in oncogenesis, acting both to suppress and facilitate neoplastic transformation. Moreover, mutations of telomerase components required for catalytic activity, TERT and TERC, are found in diseases characterized by stem cell failure including dyskeratosis congenita, subsets of aplastic anemia and idiopathic pulmonary fibrosis. Taken together, these telomerase plays a key role in maintaining telomeres, accumulating evidence suggests that the catalytic observations implicate telomerase as a critical link between cancer and aging. Although it is clear that subunit of TERT contributes to both normal and malignant cell physiology beyond its role in telomere maintenance. Specifically, expression of TERT drives tumor formation under situations when telomere length is not limiting and alters stem cell function in a manner that is independent of the expression of TERC. In prior work, we found that TERT is expressed in cycling primary pre-senescent human fibroblasts and that this low-level expression of telomerase controls proliferative lifespan. During the past funding period, we have investigated the role of TERT in both normal and malignant mammalian cells and found that in addition to its role in telomere maintenance, TERT regulates overall chromatin structure. Moreover, we and others have identified several novel protein complexes that associate with TERT. In recent work, we have found that TERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), a gene that is mutated in the inherited pleiotropic syndrome Cartilage-Hair Hypoplasia. TERT and RMRP form an RNA dependent RNA polymerase (RdRP). These new observations suggest that TERT forms several distinct enzymatic complexes and provide a foundation to understand extra-telomeric functions of TERT. This proposal focuses on investigating the role of these newly identified TERT complexes in senescence and cancer. Specifically, biochemical, genetic and molecular biological approaches will be applied to investigate the role of the TERT-RMRP RdRP in chromatin homeostasis, senescence and transformation, to understand the roles of TERT-RMRP complexes in normal cells and tissues and to elucidate the function of TERT protein complexes in the regulation of senescence. These studies will not only provide new insights into the roles of various TERT complexes in aging and cancer but will also enhance our understanding of heterochromatin regulation. In addition, these studies will provide a foundation for strategies to manipulate these complexes therapeutically. PUBLIC HEALTH RELEVANCE: Although it is clear that telomeres and telomerase play important roles in aging and cancer, we lack a complete understanding of the roles of telomerase components in senescence and transformation. This proposal focuses on deciphering the role of newly identified TERT complexes in both normal and malignant cells and tissues. These biochemical, cell and animal- based studies will not only provide insight into the biology of TERT complexes but will serve as a foundation for translational studies for the development of novel therapeutic agents.

描述（由申请人提供）：端粒稳态调节哺乳动物细胞的染色体稳定性和细胞复制寿命。因此，端粒生物学的改变在人类癌症的发病机制中起着关键作用，并可能导致衰老。事实上，人类和动物模型的研究表明，端粒和端粒酶（维持端粒结构的逆转录酶）在肿瘤发生中起双重作用，既抑制又促进肿瘤转化。此外，在以干细胞衰竭为特征的疾病中，包括先天性角化不良、再生障碍性贫血亚群和特发性肺纤维化，发现了催化活性所需的端粒酶组分TERT和TERC的突变。综上所述，这些端粒酶在维持端粒中起着关键作用，越来越多的证据表明，催化观察表明端粒酶是癌症和衰老之间的关键联系。虽然很明显，TERT亚基在正常和恶性细胞生理上的贡献超出了它在端粒维持中的作用。具体来说，TERT的表达在端粒长度不受限制的情况下驱动肿瘤形成，并以独立于TERC表达的方式改变干细胞功能。在之前的工作中，我们发现TERT在循环原发性衰老前人类成纤维细胞中表达，并且端粒酶的低水平表达控制增殖寿命。在过去的资助期内，我们研究了TERT在正常和恶性哺乳动物细胞中的作用，发现除了在端粒维持中起作用外，TERT还调节整体染色质结构。此外，我们和其他人已经确定了几种与TERT相关的新型蛋白质复合物。在最近的研究中，我们发现TERT与线粒体RNA加工核糖核酸内切酶（RMRP）的RNA组分相互作用，RMRP是遗传性多效性综合征软骨毛发发育不全中发生突变的基因。TERT和RMRP形成RNA依赖性RNA聚合酶（RdRP）。这些新的观察结果表明，TERT形成了几种不同的酶复合物，并为了解TERT的端粒外功能提供了基础。本研究的重点是研究这些新发现的TERT复合物在衰老和癌症中的作用。具体而言，将应用生化、遗传和分子生物学等方法研究TERT- rmrp RdRP在染色质稳态、衰老和转化中的作用，了解TERT- rmrp复合物在正常细胞和组织中的作用，阐明TERT蛋白复合物在衰老调控中的功能。这些研究不仅将为各种TERT复合物在衰老和癌症中的作用提供新的见解，而且将增强我们对异染色质调控的理解。此外，这些研究将为治疗性地操纵这些复合物的策略提供基础。